Lung cancer is one of the most common, most lethal, but least treatable diseases. All currently available anticancer drugs are essentially ineffective against most human lung cancers. For the purpose of therapy, lung cancers are generally classified into small cell and non-small cell cancers. With respect to the many different tumor types found in the category of non-small cell cancer, it is difficult to imagine that any one anticancer drug can be effective against all of them. This project utilizes the subclassification of cell lines by cell type and differentiation generated by Annual Report Z01 CM 07175-01 LETM to further define biological and functional aspects of these defined cell lines in vitro. Such studies include scanning and transmission electron microscopy, quantitative image analysis, detailed analysis of cytoplasmic enzymes, antigenic expression, endocrine and/or secretory activity, as well as competence for binding and metabolism of 4-ipomeanol and other candidate anticancer drugs. We found clear cut cell type specific differences for almost every parameter studies. Moreover, we found that some of the well differentiated tumor cell lines have retained biochemical pathways which are considered functional markers of their normal cells of origin. Among those were: expression of monooxygenase and other xenobiotic-metabolizing enzyme activiies (markers of normal pulmonary Clara cells) in an adenocarcinoma line with the ultrastructure of Clara cells; phospholipid biosynthesis (marker for normal alveolar type II cells) in an adenocarcinoma lne withultrastgructure of alveolar type II cells; neuroendocrine activity in several small cell cancer lines and carcinoid lines. We also found cell type specific susceptibility to drug-induced toxicity, selectively high levels of prostaglandin synthetase activity which were cell type and differentiation dependent in collaboration with other investigators within the LETM.